Iontophoretic delivery device with single lamina electrode

ABSTRACT

An electrically powered transdermal iontophoretic delivery device (10, 20) and a method of making same is provided. The device utilizes electrode assemblies (8, 9 ) composed of a substantially homogenous blend of a polymeric matrix containing about 5 to 50 vol % of a conductive filler which forms a conductive network through the matrix, and up to about 50 vol % of the agent to be iontophoretically delivered through the skin. In the case of the donor electrode assembly, the agent is typically a drug and preferably a water soluble drug salt. In the case of the counter electrode assembly, the agent is typically an electrolyte salt. The homogenous blend eliminates the need for separate electrode and agent containing layers which require lamination.

This application is a continuation Ser. No. 08/197,655, filed Feb. 17,1994, now U.S. Pat. No. 5,543,698 which is a continuation of Ser. No.667,714 filed Mar. 11, 1991, now abandoned, and benefit of the fillingdate of said earlier filed application is claimed under 35 U.S.C. §120.

TECHNICAL FIELD

This invention relates to a device for delivering an agent transdermallyor transmucosally by iontophoresis. More particularly, this inventionrelates to an electrically powered iontophoretic delivery device havinga polymer-based electrode assembly and a method of making same.

BACKGROUND ART

Iontophoresis, according to Dorland's Illustrated Medical Dictionary, isdefined to be "the introduction, by means of electric current, of ionsof soluble salts into the tissues of the body for therapeutic purposes."Iontophoretic devices have been known since the early 1900's. Britishpatent specification No. 410,009 (1934) describes an iontophoreticdevice which overcame one of the disadvantages of such early devicesknown to the art at that time, namely the requirement of a special lowtension (low voltage) source of current which meant that the patientneeded to be immobilized near such source. The device of that Britishspecification was made by forming a galvanic cell from the electrodesand the material containing the medicament or drug to be deliveredtransdermally. The galvanic cell produced the current necessary foriontophoretically delivering the medicament. This ambulatory device thuspermitted iontophoretic drug delivery with substantially lessinterference with the patient's daily activities.

More recently, a number of United States patents have issued in theiontophoresis field, indicating a renewed interest in this mode of drugdelivery. For example, U.S. Pat. No. 3,991,755 issued to Vernon et al;U.S. Pat. No. 4,141,359 issued to Jacobsen et al; U.S. Pat. No.4,398,545 issued to Wilson; and U.S. Pat. No. 4,250,878 issued toJacobsen disclose examples of iontophoretic devices and someapplications thereof. The iontophoresis process has been found to beuseful in the transdermal administration of meicaments or drugsincluding lidocaine hydrochloride, hydrocortisone, fluoride, penicillin,dexamethasone sodium phosphate, insulin and many other drugs. Perhapsthe most common use of iontophoresis is in diagnosing cystic fibrosis bydelivering pilocarpine salts iontophoretically. The pilocarpinestimulates sweat, production; the sweat is collected and analyzed forits chloride content to detect the presence of the disease.

In presently known iontophoretic devices, at least two electrodes areused. Both of these electrodes are disposed so as to be in intimateelectrical contact with some portion of the skin of the body. Oneelectrode, called the active or donor electrode, is the electrode fromwhich the ionic substance, medicament, drug precursor or drug isdelivered into the body by iontophoresis. The other electrode, calledthe counter indifferent, inactive or return electrode, serves to closethe electrical circuit through the body. In conjunction with thepatient's skin contacted by the electrodes, the circuit is completed byconnection of the electrodes to a source of electrical energy, e.g., abattery. For example, if the ionic substance to be delivered into thebody is positively charged (i.e., a cation), then the anode will be theactive electrode and the cathode will serve to complete the circuit. Ifthe ionic substance to be delivered is negatively charged (i.e., ananion), then :he cathode will be the active electrode and the anode willbe the counter electrode.

Alternatively, both the anode and cathode may be used to deliver drugsof opposite charge into the body. In such a case, both electrodes areconsidered to be active or donor electrodes. For example, the anode candeliver a positively charged ionic substance into the body while thecathode can deliver a negatively charged ionic substance into the body.

It is also known that iontophoretic delivery devices can be used todeliver an uncharged drug or agent into the body. This is accomplishedby a process called electroosmosis. Electroosmosis is the transdermalflux of liquid solvent (e.g., the liquid solvent containing theuncharged drug or agent ) which is induced by the presence of anelectric field imposed across the skin by the donor electrode. As usedherein, the terms "iontophoresis" and "iontophoretic" refer to (1) thedelivery of charged drugs or agents by electromigration, (2) thedelivery of uncharged drugs or agents by the process of electricosmosis, (3) the delivery of charged drugs or agents by the combinedprocesses of electromigration and electroosmosis, and/or (4) thedelivery of a mixture of charged and uncharged drugs or agents by thecombined processes of electromigration and electroosmosis.

Furthermore, existing iontophoresis devices generally require areservoir or source of, the beneficial agent (which is preferably anionized or ionizable agent or a precursor of such agent) to beiontophoretically delivered into the body. Examples of such reservoirsor sources of ionized or ionizable agents include a pouch as describedin the previously mentioned Jacobsen U.S. Pat. No. 4,250,878, or apre-formed gel body as described in Webster U.S. Patent No. 4,383,529and Ariura et al. U.S. Pat. No. 4,474,570. Such drug reservoirs areelectrically connected to the anode or the cathode of an iontophoresisdevice to provide a fixed or renewable source of one or more desiredagents.

More recently, iontophoretic delivery devices have been developed inwhich the donor and counter electrode assemblies have a "multi-laminate"construction. In these devices, the donor and counter electrodeassemblies are formed of multiple layers of (usually) polymericmatrices, for example, Parsi U.S. Pat. No. 4,731,049 discloses a donorelectrode assembly having hydrophilic polymer based electrolytereservoir and drug reservoir layers, a skin-contacting hydrogel layer,and optionally one or more semipermeable membrane layers. Sibalis U.S.Pat. No. 4,640,689 discloses in FIG. 6 an iontophoretic delivery devicehaving a donor electrode assembly comprised of a donor electrode (204),a first drug reservoir (202), a semipermeable membrane layer (200), asecond drug reservoir (206), and a microporous skin-contacting membrane(22'). The electrode layer can be formed of a carbonized plastic, metalfoil or other conductive films such as a metallized mylar film. Inaddition, Ariura et al, U.S. Pat. No. 4,474,570 discloses a devicewherein the electrode assemblies include a conductive resin filmelectrode layer, a hydrophilic gel reservoir layer, a currentdistribution and conducting layer and an insulating backing layer.Ariura et al disclose several different types of electrode layersincluding an aluminum foil electrode, a carbon fiber non-woven fabricelectrode and a carbon-containing rubber film electrode.

Transdermal iontophoretic delivery devices having electrodes composed ofelectrochemically inert materials, as well as devices having electrodescomposed of electrochemically reactive materials are known. Examples ofelectrochemically inert electrode materials include platinum, carbon,gold and stainless steel. The prior art has also recognized that theelectrochemically reactive electrode materials are in many casespreferred from the standpoint of drug delivery efficiency and pHstability. For example, U.S. Pat. Nos. 4,744,787; 4,747,819 and4,752,285 all disclose iontophoretic electrodes composed of materialswhich are either oxidized or reduced during operation of the device.Particularly preferred electrode materials include silver as the anodicelectrode, and silver chloride as the cathodic electrode.

Others have suggested using biomedical electrodes having currentdistribution members composed of a rubber or other polymer matrix loadedwith a conductive filler such as powdered metal. See for example, U.S.Pat. No. 4,367,745. Such films however, have several disadvantages.First, as the metal particle loading in a polymer matrix approachesabout 65 vol %, the matrix begins to break down and becomes too brittleto be handled. Even at metal particle loadings only about 50 to 60 vol%, the films produced are extremely rigid and do not confirm well tonon-planar surfaces. This is a particular disadvantage when designing anelectrode adapted to be worn on the skin or a mucosal membrane. Aniontophoretic electrode adapted to be worn on a body surface must havesufficient flexibility to Contour itself to the natural shape of thebody surface to which it is applied.

The drug and electrolyte reservoir layers of iontophoretic deliverydevices have been formed of hydrophilic polymers. See for example,Ariura et al, U.S. Pat. No. 4,474,570; Webster U.S. Pat. No. 4,383,529and Sasaki U.S. Pat. No. 4,764,164. There are several reasons for usinghydrophilic polymers. First, water is the preferred solvent for ionizingmany drug salts. Secondly, hydrophilic polymer components i.e., the drugreservoir in the donor electrode and the electrolyte reservoir in thecounter electrode) can be hydrated while attached to the body byabsorbing water from the skin (i.e., through transepidermal water lossor sweat) or from a mucosal membrane (e.g., by absorbing saliva in thecase of oral mucosal membranes). Once hydrated, the device begins todeliver ionized agent to the body. This enables the drug reservoir to bemanufactured in a dry state, giving the device a longer shelf life.

Hydrogels have been particularly favored for use as the drug reservoirmatrix and electrolyte reservoir matrix in iontophoretic deliverydevices, in part due to their high equilibrium water content and theirability to quickly absorb water. In addition, hydrogels tend to havegood biocompatibility with the skin and with mucosal membranes. In spiteof these advantages however, hydrogels and other hydrophilic polymercomponents are difficult to laminate to other components of the deliverysystem. For example, when utilizing a drug reservoir matrix or anelectrolyte reservoir matrix composed of a hydrophilic polymer, thematrix begins to swell as it absorbs water from the skin. In the case ofhydrogels, the swelling is quite pronounced. Typically, the drug orelectrolyte reservoir is in either direct contact, or contact through athin layer of an electrically conductive adhesive, with an electrode.Typically, the electrode is composed of metal (e.g., a metal foil or athin layer of metal deposited on a backing layer) or a hydrophobicpolymer containing a conductive filler (e.g., a hydrophobic polymerloaded with carbon fibers and/or metal particles). The electrodes (i.e.,either metal electrodes or hydrophobic polymers containing a conductivefiller), on the other hand, do not absorb water and tend not to swell.The different swelling properties of the hydrophilic reservoirs and theelectrodes results in separation along their contact surfaces. In severecases, this separation can result in the complete loss of electricalcontact between the electrode layer and the reservoir layer resulting inan inoperable device.

In general, the greater the number of layers in a multi-laminate typeelectrode assembly, the greater is the likelihood of a system failuredue to loss of:electrical contact between adjacent electrode assemblylayers. Furthermore, the greater the number of electrode assemblylayers, the more complicated the assembling/manufacturing processwherein each of the individual layers must be consecutively laminated,one onto the next.

DISCLOSURE OF THE INVENTION

It is an object of this invention to provide an improved electrodeassembly for an iontophoretic delivery device.

It is another object of this invention to provide an electrode assemblyhaving fewer individual layers or laminae, and therefore having areduced likelihood of electrical failure between adjacent layers.

It is a further object of this invention to provide a method of makingan improved electrode assembly for an iontophoretic delivery device.

These and other objects are met by an electrically powered iontophoreticdelivery device including a donor electrode assembly, a counterelectrode assembly and a source of electrical power adapted to beelectrically connected to the donor and counter electrode assemblies.The donor and counter electrode assemblies are adapted to be placed inagent transmitting relation with a body surface. At least One of thedonor and counter electrode assemblies comprises a substantiallyhomogenous blend of a polymeric matrix containing about 5 to 50 vol % ofa conductive filler which forms a conductive network through the matrix,and from about 1 to 50 vol % of an agent to be iontophoreticallydelivered through the body surface.

Preferably, the polymeric matrix contains about 15 to 30 vol %conductive filler and about 10 to 50 vol % of the agent. Mostpreferably, the polymeric matrix contains about 20 to 25 vol % of theconductive filler and about 20 to 35 vol % of the agent. In the case ofthe donor electrode assembly, the agent is most preferably a drug orother therapeutic agent. In the case of the counter electrode assembly,the agent is most preferably an electrolyte salt.

Also provided is a method of making an electrode assembly for anelectrically powered iontophoretic delivery device. The method comprisesthe steps of homogenously blending about 5 to 50 vol % of a conductivefiller, and from about 1 to about 50 vol % of an agent to beiontophoretically delivered, into a polymeric matrix until the fillerforms an electrically conductive network through the polymer matrix. Themethod further includes the step of forming the agent-containing blendedmixture into a sheet. Preferably, the blending and sheet forming stepsare performed in a rubber mill. Optionally, the sheet so obtained iscalendered to a uniform desired final thickness.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of an iontophoretic drug delivery deviceaccording to the present invention;

FIG. 2 is a schematic view of another embodiment of an iontophoreticdelivery device according to the present invention;

FIG. 3 is a side sectional view of another embodiment of aniontophoretic electrode assembly;

FIG. 4 is a schematic view of an apparatus used to make an electrodeassembly according to the present invention; and

FIG. 5 is a graph of in vitro transdermal drug flux from an electrodeassembly over time.

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 is a schematic view of an iontophoretic delivery device 10 fordelivering a beneficial agent through a body surface 22. Body surface 22is typically intact skin or a mucosal membrane. Iontophoretic deliverydevice 10 includes a donor electrode assembly 8, a counter electrodeassembly 9, an electrical power source 27 (e.g., a battery) and anoptional control circuit 19.

The donor electrode assembly 8 contains the beneficial agent (e.g., adrug) to be iontophoretically delivered by device 10.

The donor electrode assembly 8 is shown adhered to the body surface 22by means of an ion-conducting adhesive layer 17.

Iontophoretic delivery device 10 includes a counter electrode assembly 9which is placed on the body surface 22 at a location spaced apart fromelectrode assembly 8. Counter electrode assembly 9 is shown adhered tothe body surface 22 by means of an ion-conducting adhesive layer 18. Thedonor and counter electrode assemblies 8 and 9 normally include astrippable release liner, not shown, which is removed prior toapplication of electrode assemblies 8 and 9 to body surface 22. Counterelectrode assembly 9 contains a pharmacologically acceptable electrolytesalt. Suitable electrolytes for electrode assembly 9 include sodiumchloride, alkaline salts, chlorides, sulfates, nitrates, carbonates,phosphates, and organic salts such as ascorbates, citrates, acetates andmixtures thereof. Electrode assembly 9 may also contain a bufferingagent. Sodium chloride is a suitable electrolyte when the counterelectrode assembly 9 is the cathode and is composed of silver/silverchloride, optionally with a sodium phosphate buffer.

When the device 10 is in Storage, no current flows because the deviceforms an open circuit. When the device 10 is placed on the skin ormucosal membrane of a patient, and the electrode assemblies 8 and 9become sufficiently hydrated to allow movement of ions therethrough, thecircuit between the electrodes is closed and the power source begins todeliver current through the device and through the body of the patient.Electrical current flowing through the conductive members 11,12 and 13of the device 10 (i.e., those portions used to connect the power source27 to the electrode assemblies 8 and 9) is carried by electrons(electronic conduction), while current flowing through the hydratedportions of the device 10 (e.g., the donor electrode assembly 8, thecounter electrode assembly 9 and the ion-conducting adhesive layers 17and 18) is carried by ions (ionic conduction). In order for current toflow through the device, it is necessary for electrical charge to betransferred from current carrying members 11 and 12 to chemical speciesin solution in electrode assemblies 8 and 9, respectively, by means ofoxidation and reduction charge transfer reactions. The type of chargetransfer reaction occurring within electrode assembly 8 or 9 will dependin part upon the polarity of the electrode assembly as well as thecomposition of the conductive filler added to the electrode assembly, aswill be discussed in more detail hereinafter.

Electrode assemblies 8 and 9 are each comprised of a polymeric matrixcontaining a conductive filler and an agent (e.g., a drug or anelectrolyte) to be iontophoretically delivered during operation of thedevice. Any polymer which can be suitably mixed with the conductivefiller and the agent may be used as the polymeric matrix of electrodeassemblies 8 and 9. Both hydrophilic and hydrophobic polymers can beused as the matrix of electrode assemblies 8 and 9. In addition,mixtures of hydrophilic and hydrophobic polymers may also be used.Examples of suitable polymers for use as the matrix of electrodeassemblies 8 and 9 include, without limitation, polyalkenes,polyisoprenes, rubbers, polyvinylacetate, ethylene vinyl acetatecopolymers, polyamides, polyurethanes, polyvinylchloride, polyvinylpyrrolidones, cellulosic polymers, polyethylene oxides, polyacrylic acidpolymers and mixtures thereof. A preferred polymeric matrix forelectrode assemblies 8 and 9 is a mixture of: (1) a copolymer ofethylene vinyl acetate and (2) polyvinyl pyrrolidone.

The polymeric matrix of electrode assemblies 8 and 9 should containabout 5 to 50 vol %, preferably about 15 to 30 vol %, and mostpreferably about 20 to 25 vol % of a conductive filler which forms aconductive network through the polymeric matrix. The conductive fillerforming the conductive network in the polymeric matrix may be comprisedof either an electrochemically inert conductive material, anelectrochemically reactive conductive material or a mixture thereof. Asmentioned above, as electrical current flows through device 10 oxidationof some chemical species takes place within one of the electrodeassemblies 8 and 9, while reduction of some chemical species takes placewithin the other electrode assembly. In cases where the conductivefiller is comprised entirely of an electrochemically inert materialwhich is unable to undergo oxidation or reduction during operation ofthe device, the water used to hydrate electrode assemblies 8 and 9 willbe electrolyzed during operation of device 10. Unfortunately, theelectrolysis of water results in the production of protons at the anodicelectrode assembly and hydroxyl ions at the cathodic electrode assembly;In addition, gaseous hydrogen and oxygen are involved at the cathodicand anodic electrode assemblies, respectively. Since the electrolysis ofwater produces protons and hydroxyl ions, it is important to provideeither appropriate buffers or to utilize an appropriate form of a drug,i.e., either an acid or base type drug when using exclusivelyelectrochemically inert conductive fillers. For example, when the agentto be delivered i s a base (e.g., lidocaine, nicotine, etc.) theproduction of protons within the anodic donor electrode assembly 8 willact to convert the base to an ionizable (e.g., salt) form Which can bedelivered from the device by electromigration. Similarly, when the agentto be delivered is an acid (e.g., cromolyn) the production of hydroxylions within the cathodic donor electrode assembly 8 will act to convertthe acid to an ionizable (e.g., salt) form which can likewise bedelivered from the device by electromigration.

Alternatively, and in many cases preferably, the conductive filler willbe comprised, at least in part, of a material which is electrochemicallyreactive and participates in a charge transferring chemical reaction.Examples of preferred electrochemically reactive conductive fillersinclude silver, zinc, copper and silver chloride. The preferredoxidation/reduction reactions for these materials are shown below:

    Ag⃡Ag.sup.+ +e.sup.-

    Zn⃡Zn.sup.+2 +2e.sup.-

    Cu⃡Cu.sup.+2 +2e.sup.-

    Ag+Cl.sup.- ⃡AgCl+e.sup.-

where the forward reaction is the oxidation reaction taking place at theanodic electrode and the reverse reaction is the reduction reactiontaking place at the cathodic electrode. Other standard electrochemicalreactions and their respective reduction potentials are well known inthe art. See the CRC Handbook of Chemistry and Physics, pp D 151-58,67th edition (1986-1987).

If the electrode assembly is to be used as an anode, theelectrochemically reactive conductive filler preferably is a chemicalspecies able to undergo oxidation during operation of the device.Suitable chemical species able to undergo oxidation include metals suchas silver, zinc, copper, nickel, tin, lead, iron, chromium and otheroxidizable species listed in the CRC Handbook of Chemistry and Physics,57th edition, D-141 to D-146. Preferred chemical species able,to undergooxidation are metals, preferably in the form of powders. Most preferredare silver and zinc powders.

If the electrode assembly is to be used as a cathode, theelectrochemically reactive conductive filler preferably is a chemicalspecies able to undergo reduction during operation of the device.Suitable chemical species which are able to undergo reduction includesilver chloride, silver bromide, silver hexacyanoferrate, and otherreducible species listed in the CRC Handbook of Chemistry and Physics,57th edition, D-141 to D-146. Of these, silver chloride is mostpreferred.

The donor and counter electrode assemblies each contain from about 1 to50 vol % of an agent to be iontophoretically delivered through the bodysurface. Preferably, the polymeric matrix contains from about 10 to 50vol % of the agent and most preferably from about 20 to 35 vol % of theagent. As used herein, the expression "agent" can mean a drug or otherbeneficial therapeutic agent when referring to the donor electrodeassembly or an electrolyte salt when referring to the counter electrodeassembly.

The electrode assemblies 8 and 9 can be formed by blending the desiredagent (i.e., the drug or electrolyte), the conductive filler or fillersand other component(s), with the polymer by melt blending the conductivefiller and agent into the polymer matrix and then casting the blend intoa film using known solvent casting techniques, for example. On aCommercial scale however, the electrode assemblies 8 and 9 arepreferably formed by pre-blending the conductive filler and agent intothe polymer matrix in a mixer such as a Banbury mixer and then passingthe pre-blended material through a rubber mill. Rubber milling involvesrepeatedly passing the materials through the nip of two rolls rotatingat different speeds and in opposite directions. This method has beenfound to be particularly suitable when using a combination of carbonfibers and powdered metal as the conductive filler. In general, thematerial must be passed through multiple rubber mills, or alternatively,must be passed a number of times through a single rubber mill in orderto achieve effective blending of the agent and conductive fillerthroughout the polymer matrix. Following the last rubber milling step,the material is preferably passed through one or more calendar rolls inorder to obtain a precise film thickness.

FIG. 4 is a schematic illustration of an apparatus used to manufacturethe electrode assemblies of the present invention. The conductivefiller, the agent and the polymer are first pre-blended in a suitablecommercial mixer 47 such as a Banbury mixer or similar device. Thepre-blended material is then fed into hopper 41 of mill 42. For example,the material fed into hopper 41 can be in the form of chunks ofpre-blended polymer containing incompletely blended agent and fillertherein. As mentioned above, mill 42 may contain one or more sets ofopposed rollers rotating at different speeds and in differentdirections. In the case of a single mill (i.e., a single set of opposedrollers), the operator must recycle the milled material back through therollers until the agent and the filler(s) are homogenously blendedthroughout the polymer matrix. In the case where mill 42 contains aplurality of sets of opposed rollers, the material can be successivelymilled on a continuous basis until the filler(s) and the agent arehomogenously blended throughout the polymer matrix.

A sheet 50 of the blended material is formed after passing through thelast pair of opposing rollers in the rubber mill 42. Sheet 50 passesover roller 43 and is fed into a series of calender rolls 44, 45, and46. ! Calender rolls 44, 45, 46 are preferably heated. The temperatureto which the calender rolls are heated will depend in large part on thespecific polymer matrix used as well as the specific fillers blendedtherein. For example, when using an EVA 9 polymer matrix containingcarbon fibers and/or silver powder, the calender rolls are typicallyheated to a temperature in the range of about 120° C. to 130° C. Anotherexample is a polyisobutylene polymer matrix containing the sameconductive fillers. The polyisobutylene film is typically heated to atemperature in the range of about 30° C. to 90° C. The calender rollsare preferably operated at a nip pressure of at least about 2000 psig.The final sheet 50 emerging from calender rolls 46 has an extremelyuniform thickness, generally though not necessarily within the range ofabout 0.05 to 0.15 ±0.005 mm, with excellent blending of filler andagent throughout the polymer sheet.

FIG. 2 illustrates another iontophoretic delivery device designated bythe numeral 20. Like device 10, device 20 also contains an electricalpower source 27 (e.g., a battery) and an optional control circuit 19.However, in device 20 the donor electrode assembly 8 and the counterelectrode assembly 9 are physically attached to insulator 26 and form asingle self-contained unit. Insulator 26 prevents the electrodeassemblies 8 and 9 from short circuiting by preventing electrical and/orion transport between the electrode assemblies 8 and 9. Insulator 26 ispreferably formed of a hydrophobic non-conducting polymeric materialwhich is impermeable to both the passage of ions and water. A preferredinsulating material is a nonporous ethylene vinyl acetate copolymer.

Alternatively, both the donor electrode assembly 8 and the counterelectrode assembly 9 may be used to iontophoretically deliver differentbeneficial agents through body surface 22. For example, positive agentions can be delivered through body surface 22 from the anodic electrodeassembly, while negative agent ions can be delivered from the catholicelectrode assembly. Alternatively, neutral drugs can be introduced fromeither electrode assembly by electroosmosis.

As an alternative to the side-by-side alignment of the donor electrodeassembly 8, the insulator 26 and the counter electrode assembly 9 shownin FIG. 2, the electrode assemblies can be concentrically aligned withthe counter electrode assembly positioned centrally and surrounded bythe insulator 26 and the donor electrode assembly. The electrodeassemblies can, if desired, be reversed with the counter electrodeassembly surrounding the centrally positioned donor electrode assembly.The concentric alignment of the electrode assemblies can be circular,elliptical, rectangular or any of a variety of geometric configurations.

In one alternate embodiment shown in FIG. 3, electrode assembly 8 has aplurality of fluid flow pathways 30 running therethrough. Pathways 30can be formed by any number of known means such as by punching theelectrode assembly 8 after it is made or by forming the pathways at thetime the electrode is made (e.g., by molding) using a mold insert.Alternatively, the pathways 30 in electrode assembly 8 (or electrodeassembly 9) can be formed by mixing a sufficient quantity, generallyabout 10 to 50 vol %, preferably about 20 to 35 vol % and mostpreferably about 25 to 30 vol %, of a pore forming agent throughout thematrix of electrode assembly 8. In all of these cases, a plurality ofpathways through the electrode assembly 8 are formed which can carry asolvent, such as water, therethrough. The electrode of FIG. 3 has anadditional advantage in that it permits the delivery device, andspecifically the electrode assemblies, to be manufactured in anon-hydrated Condition, thereby giving the device a longer and morestable shelf life. Water, and/or another liquid solvent, can be appliedto the electrode surface at the time of use. The pore forming agentsorbs solvent (e.g., water) thereby allowing water transport along aplurality of fluid flow pathways 30 through the "porous" electrodeassembly matrix to hydrate electrode assembly(s) and place the device inan operational (i.e., hydrated) condition.

The pore-formers useful for forming the pathways 30 in electrodeassemblies 8 and 9 include solids and pore-forming liquids. Theexpression pore-forming liquids generically embraces semi-solids andviscous fluids. The term pore-former for both solids and liquidsincludes substances that can be dissolved, extracted or leached from theelectrode by a fluid, preferably water, to form an open-cell type porousstructure. Additionally, the pore-formers suitable for the inventioninclude pore-formers that can be dissolved, leached, or extractedwithout causing physical or chemical changes in the electrode polymermatrix. The pore-forming solids generally have a size of about 0.1 to200 microns and they include alkali metal salts such as lithiumcarbonate, sodium chloride, sodium bromide, sodium carbonate, potassiumchloride, potassium sulfate, potassium phosphate, sodium benzoate,sodium acetate, sodium citrate, potassium nitrite, and the like; thealkaline earth metal salts such as calcium phosphate, calcium nitrate,calcium chloride, and the like; the transition metal salts such asferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,manganese fluoride, manganese fluorosilicate, and the like; organiccompounds such as polysaccharides including the sugars sucrose, glucose,fructose, mannitol, mannose, galactose, aldohexose, altrose, talose,sorbitol and the like. The pore formers can also be soluble polymerssuch as starch-graft poly(Na acrylate co-acrylamide) polymers,Carbowaxes®, CarboPol®, and the like. Preferred pore formers arestarch-graft poly (Na-acrylate co-acrylamide) polymers sold under thetrade name Waterlock® by Grain Processing Corp., Muscatine, Iowa. Thepore-formers are non-toxic and form fluid flow pathways 30 through theelectrode matrix. The pathways 30 are effective to convey water and/orother liquid solvent to the underlying drug or electrolyte reservoir,enabling the underlying reservoir to be quickly hydrated using anexternal source of liquid solvent (e.g., water) for quick start-up ofthe device.

Power source 27 is typically one or more batteries. As an alternative toa battery, device 10 can be powered by a galvanic couple formed by thecurrent carrying member 11 and current carrying member 12 being composedof dissimilar electrochemical couples and being placed in electricalcontact with one other. Typical materials for delivering a cationicagent into the body include a zinc donor current carrying member 11 anda silver/silver chloride current carrying member 12. A Zn-Ag/AgClgalvanic couple provides an electrical potential of about 1 volt.

Suitable polymers for use; as the matrix of electrode assemblies 8 and 9include, without limitation, hydrophobic polymers such as polyethylene,polypropylene, polyisoprenes and polyalkenes, rubbers such aspolyisobutylene, copolymers such as Kraton®, polyvinyl acetate, ethylenevinyl acetate copolymers, polyamides including nylons, polyurethanes,polyvinylchloride, cellulose acetate, cellulose acetate butyrate,ethylcellulose, cellulose acetate, and blends thereof; and hydrophilicpolymers such as hydrogels, polyethylene oxides, Polyox®, Polyox®blended with polyacrylic acid or Carbopol®, cellulose derivatives suchas hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, pectin, starch, guar gum, locust bean gum, and the like, andblends thereof.

The adhesive properties of the electrode assemblies 8 and 9 may beenhanced by adding a resinous tackifier. This is especially importantwhen using a non-tacky polymeric matrix. Examples of suitable tackifiersinclude products sold under the trademarks Staybelite Ester #5 and #10,Regal-Rez and Piccotac, all of Hercules, Inc. of Wilmington, Del.Additionally, the matrix may contain a theological agent suitableexamples of which include mineral oil and silica.

The expressions "drug" and "therapeutic agent" are used interchangeablyand are intended to have their broadest interpretation as anytherapeutically active substance which is delivered to a living organismto produce a desired, usually beneficial, effect. In general thisincludes therapeutic agents in all of the major therapeutic areasincluding, but not limited to, anti-infectives such as antibiotics andantiviral agents, analgesics including fentanyl, sufentanil,buprenophine and analgesic combinations, anesthetics, anorexics,antiarthritics, antiasthmatic agents such as terbutaline,anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals,antihistamines, anti-inflammatory agents, antimigraine preparations,antimotion sickness preparations such as scopolamine, ondansetron andgranisetron, antinauseants, antineoplastics, antiparkinsonism drugs,antipruritics, antipsychotics, antipyretics, antispasmodics, includinggastrointestinal and urinary, anticholinergics, sympathomimetrics,xanthine derivatives, cardiovascular preparations including calciumchannel blockers such as nifedipene, beta-blockers, beta-agonists suchas dobutamine and ritodrine, antiarrythmics, antihypertensives such asatenolol, ACE inhibitors such as rinitidine, diuretics, vasodilators,including general, coronary, peripheral and cerebral, central nervoussystem stimulants, cough and cold preparations, decongestants,diagnostics, hormones such as parathyroid hormone, hypnotics,immunosuppressives, muscle relaxants, parasympatholytics,parasympathomimetrics, prostaglandins, proteins, peptides,psychostimulants, sedatives and tranquilizers.

The invention is also useful in the controlled delivery of peptides,polypeptides, proteins and other macromolecules. These macromolecularsubstances typically have a molecular weight of at least about 300daltons, and mote typically a molecular weight in the range of about 300to 40,000 daltons. Specific examples of peptides and proteins in thissize range include, without limitation, LHRH, LHRH analogs Such asbuserelin, gonadorelin, naphrelin and leuprolide, GHRH, insulin,insulotropin, heparin, calcitonin, octreotide, endorphin, TRH, NT-36(chemical name:N=[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide),liprecin, pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate,etc.), follicle luteoids, αANF, growth factors such as growth factorreleasing factor (GFRF), βMSH, somatostatin, bradykinin, somatotropin,platelet-derived growth factor, asparaginase, bleomycin sulfate;chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin(ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor),glucagon, hirulog, hyaluronidase, interferon, interleukin-2, menotropins(urofollitropin (FSH) and LH), oxytocin, streptokinase, tissueplasminogen activator, urokinase, vasopressin, desmopressin, ACTHanalogs, ANP, ANP clearance inhibitors, angiotensin II antagonists,antidiuretic hormone agonists, antidiuretic hormone antagonists,bradykinin antagonists, CD4, ceredase, CSF's, enkephalins, FABfragments, IgE peptide suppressors, IGF-1, neurotrophic factors, colonystimulating factors, parathyroid hormone and agonists, parathyroidhormone antagonists, prostaglandin antagonists, pentigetide, protein C,protein S, renin inhibitors, thymosin alpha-1, thrombolytics, TNF,vaccines, vasopressin antagonist analogs, alpha-1 anti-trypsin(recombinant), TGF-beta. It is most preferable to use a water solublesalt of the drug or agent to be delivered.

The combined skin-contacting areas of electrode assemblies 8 and 9 canvary from less than 1 cm² to greater than 200 cm². The average device 10however, will have electrode assemblies with a combined skin-contactingarea within the range of about 5-50 cm².

As an alternative to the ion-conducting adhesive layers 17 and 18 shownin FIGS. 1 and 2, the iontophoretic delivery devices 10 and 20 may beself-adhering to the skin in cases where the polymer matrix issufficiently tacky, either alone or by addition of suitable tackifyingresins. Another alternative to, or to supplement the adhesiveness of,the ion-conducting adhesive layers 17 and 18 is an adhesive overlay. Anyof the conventional adhesive overlays used to secure passive transdermaldelivery devices to the skin may be used Another alternative/supplementto the ion-conducting adhesive layers 17 and 18 is a peripheral adhesivelayer surrounding electrode assemblies 8 and/or 9 allowing electrodeassemblies 8 and/or 9 to have a surface in direct contact with thepatient's skin.

Having thus generally described our invention, the following exampleswill illustrate preferred embodiments thereof.

EXAMPLE I

An anodic electrode assembly was made by mixing powdered silver andgraphite fibers into an ethylene vinyl acetate copolymer matrix. First,21.4 g of ethylene vinyl acetate copolymer having a vinyl acetatecontent of 9% (EVA 9) were added to a 50 cm³ Brabender mixer (BrabenderInstruments, Inc., South Hackensack, N.J.). The mixer bowl was preheatedto 90° C. and the blade speed was set at 20 rpm. The EVA 9 polymer wasmixed for about five minutes until all of the pellets had been fused.Thereafter, 15.2 g of graphite fibers having a diameter of 8 microns anda length of 6.4 mm were slowly added into the mixer over a period ofabout five minutes. Thereafter, 70.9 g of silver powder having anaverage particle size of 4 microns was added to the mixer over a periodof about five minutes. Thereafter, 9.0 g of metoclopramidemonohydrochloride (catalog No. M0763, sold by Sigma Chemical Company ofSt. Louis, Mo.) were slowly added to the mixer over a period of aboutfive minutes. Thereafter, the blade speed was increased to 40 rpm for anadditional 20 minutes of mixing.

The blended material (about 180 cm³) was then loaded into a melt pressto produce a melt pressed film. The press had two platens which could beheated or cooled by circulating water/steam therethrough. The platenswere heated to a temperature of 120° C. and the film was pressed at apressure of 3000 psi. Periodically, the pressure was momentarilyreleased in order to release air bubbles from the film. The melt pressedfilm was then passed between opposing calender rolls heated to about 95°C. The calendered film had a thickness of 6 mils.

Experiments were conducted to evaluate the drug delivery performance ofthe single lamina anodic film electrode assembly in comparison with thedrug delivery performance of two different multi-lamina type electrodeassemblies having separate and distinct electrode and drug reservoirlayers. The apparatus used to measure the electrochemical performance ofthe electrodes included a two compartment diffusion cell having humancadaver skin clamped in the opening between the two compartments. Acathode containing silver chloride was mounted within the receptorcompartment which was then filled with Dulbecco's phosphate bufferedsaline (pH 7). The single lamina anodic electrode assembly was attachedto the skin sample on the donor side of the cell. The single laminaelectrode assembly was fastened to the skin sample using an ionconducting adhesive composed of 80 vol % silicon adhesive and 20 vol %of a starch-graft poly (Na-acrylate co-acryl amide) polymer (Waterlock®,sold by Grain Processing Corp., Muscatine, Iowa). The flux ofmetoclopramide through the cadaver skin into the receptor solution wasmeasured over a period of 25 hours using UV spectroscopy. The electrodeswere connected in series with a potentiostat set to supply the necessaryvoltage to maintain a constant current level of 130 μA through thecircuit. The skin contacting area was 1.3 cm² so the current density was100 μA/cm².

A first comparative test used the same apparatus and test conditionsdescribed above except the single layer anodic electrode was replacedwith a multi-lamina electrode assembly having an electrode layercomprised of an EVA 9 polymer matrix containing 25 vol % silver powderand 20 vol % carbon fibers. A second layer was comprised of a rayonpolyester fabric. A third layer comprised of 40 vol % EVA 29, 25 vol %polyvinylpyrrolidone and 35 vol % metoclopramide HCl was the drugreservoir layer. The drug reservoir layer was adhered to the skin sampleusing the same ion conducting adhesive describe above.

A second comparative test used the same apparatus and test conditionsdescribed above except the anodic electrode was a multi-lamina electrodeassembly having separate electrode and drug reservoir layers. Theelectrode layer was comprised of an EVA 9 polymer matrix loaded with 25vol % silver powder and 20 vol % carbon fibers. The drug reservoir layerwas comprised of a rayon polyester fabric soaked with a 0.1 wt % aqueoussolution of metoclopramide HCl. The drug reservoir layer was adhered tothe skin sample using the same ion Conducting adhesive described above.

The metoclopramide flux from both the single lamina and the multi-laminaelectrode assemblies over time is shown in FIG. 4. As can be seen, thedrug flux from the single lamina electrode assembly was at least as highit not higher than the drug flux from the multi-lamina electrodeassemblies. Thus, the single lamina electrode assembly delivers drug asefficiently as the multi-lamina electrode assemblies but without theattendant risk of electrical failure between adjacent electrode assemblylayers. Furthermore, because the electrode assembly is comprised of asingle homogenous layer, the steps required to manufacture the electrodeassembly are greatly simplified in comparison with the manufacture of amulti- lamina electrode assembly.

Having thus generally described our invention and described in detailcertain preferred embodiments thereof, it will be readily apparent thatvarious modifications to the invention may be made by workers skilled inthe art without departing from the scope of this invention and which islimited only by the following claims.

What is claimed is:
 1. An electrically powered iontophoretic deliverydevice including a donor electrode assembly adapted to be placed inagent transmitting relation with a body surface, a counter electrodeassembly adapted to be placed in agent transmitting relation with a bodysurface and a source of electrical power adapted to be electricallyconnected to the donor electrode assembly and the counter electrodeassembly, wherein the donor electrode assembly comprisesa polymericmatrix having a predetermined thickness, said matrix havinghomogeneously blended therein: about 5 to 50 vol % of a conductivefiller forming a conductive network through the entire thickness of thematrix; and about 1 to 50 vol % of a therapeutic agent to beiontophoretically delivered through the body surface in order to obtaina therapeutic effect.
 2. The device of claim 1, wherein the polymericmatrix is selected from the group consisting of hydrophilic polymers,hydrophobic polymers and blends thereof.
 3. The device of claim 2,wherein the polymeric matrix is comprised of a hydrophobic polymerselected from the group consisting of ethylene vinyl acetate copolymers,polyalkylenes, polyisoprenes, rubbers, polyisobutylene,polyvinylacetate, polyamides, polyurethanes, polyvinylchlorides, andmodified cellulosic polymers.
 4. The device of claim 2, wherein thepolymeric matrix is comprised of a hydrophilic polymer selected from thegroup consisting of hydrogels, polyethylene oxides, cellulosic polymers,polyacrylic acids and polyvinyl pyrrolidones.
 5. The device of claim 2,wherein the polymeric matrix comprises polyvinyl pyrrolidone.
 6. Thedevice of claim 1, wherein the polymeric matrix comprises an ethylenevinyl acetate copolymer.
 7. The device of claim 1, containing about 15to 30 vol. % of the conductive filler.
 8. The device of claim 1,containing about 20 to 25 vol. % of the conductive filler.
 9. The deviceof claim 1, wherein the conductive filler comprises an electrochemicallyreactive material able to undergo oxidation or reduction duringoperation of the device.
 10. The device of claim 9, wherein theelectrochemically reactive material is selected from the groupconsisting of Ag, Zn, Cu, silver halides, copper halides and Ag₄Fe(CN)₆.
 11. The device of claim 1, wherein the conductive fillercomprises an electrochemically inert material.
 12. The device of claim11, wherein the conductive filler is selected from the group consistingof carbon or graphite fibers, powdered carbon or graphite andelectrochemically inert metals.
 13. The device of claim 12, wherein theinert metal is selected from the group consisting of platinum,palladium, gold and stainless steel.
 14. The device of claim 1, whereina plurality of fluid flow pathways are provided through the electrodeassembly.
 15. The device of claim 14, wherein the fluid flow pathwaysare provided by a soluble pore forming agent in the polymeric matrix.16. The device of claim 1, containing about 10 to 50 vol % of thetherapeutic agent.
 17. The device of claim 1, containing about 20 to 35vol % of the therapeutic agent.
 18. The device of claim 1, wherein thepolymeric matrix comprised of about 10 to 60 wt % of a hydrophilicpolymer and about 10 to 60 wt % of a hydrophobic polymer.
 19. The deviceof claim 1, wherein the power source comprises a battery.